tbuckley/cabot-search huggingface dataset:
Estrogen Receptor Signaling in the Immune System
Authors: Binita Chakraborty, Jovita Byemerwa, Taylor Krebs, Felicia Lim, Ching-Yi Chang, Donald P McDonnell
Journal: Endocrine Reviews (2022)

The immune system functions in a sexually dimorphic manner, with females exhibiting more robust immune responses than males. However, how female sex hormones affect immune function in normal homeostasis and in autoimmunity is poorly understood. In this review, we discuss how estrogens affect innate and adaptive immune cell activity and how dysregulation of estrogen signaling underlies the pathobiology of some autoimmune diseases and cancers. The potential roles of the major circulating estrogens, and each of the 3 estrogen receptors (ERα, ERβ, and G-protein coupled receptor) in the regulation of the activity of different immune cells are considered. This provides the framework for a discussion of the impact of ER modulators (aromatase inhibitors, selective estrogen receptor modulators, and selective estrogen receptor downregulators) on immunity. Synthesis of this information is timely given the considerable interest of late in defining the mechanistic basis of sex-biased responses/outcomes in patients with different cancers treated with immune checkpoint blockade. It will also be instructive with respect to the further development of ER modulators that modulate immunity in a therapeutically useful manner.
Abstract 5644: Activation of p53 in prolonged prometaphase
Authors: Megan Anderson, Aime A. Levesque
Journal: Cancer Research (2022)

Abstract The tumor suppressor p53 plays a critical role in protecting cells from aberrant divisions in the face of DNA damage, and while its role in DNA damage checkpoints have been extensively studied, its role in the mitotic checkpoint is less well characterized. The mitotic checkpoint prevents completion of mitosis until chromosomes have made bipolar kinetochore attachments to microtubules. Previous studies have shown that cells that experience a prolonged prometaphase(&amp;gt;1.5 h) following treatment with microtubule destabilizing drugs will arrest in G1 following eventual exit from mitosis. Given its role in DNA damage checkpoints, p53 appears to be a likely candidate for involvement in this arrest. The goal of the current study is to investigate the role of p53 in this G1 arrest following prolonged prometaphase. Three cells lines were utilized:MCF10A, MCF10A/αp53 which overexpressed shRNA to p53, and MCF10A/OD which overexpresses the p53 oligomerization domain. Cells were treated with 9 μM RO-3306 for 18 h to synchronize cells at the G2/M transition. The RO-3306 was then removed and cells were treated with a microtubule destabilizing drug, nocodazole, at a concentration of 0.08 μM for 1.5 or 2.5 h to cause prometaphase arrest. The cells were then washed to remove nocodazole, and the cells were harvested at various time points and analyzed via flow cytometry and Western blot. Flow cytometry analysis in in all three cell lines showed an accumulation of cells in G1 at 12 hours in for both treatment times (1.5 and 2.5 h), with subsequent increases in sub-G1 populations by 24 hours. Western blot analysis revealed activation of p53 by phosphorylation of ser20 and activation of p21 in the MCF10A and MCF10A/OD, but not in the MCF10A/αp53 for both treatment times. Taken together, these results suggest that activation of p53 alone is not sufficient to elicit the G1 arrest, as the MCF10A/αp53 cells arrested in G1 despite the absence of p53 protein. Citation Format: Megan Anderson, Aime A. Levesque. Activation of p53 in prolonged prometaphase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5644.
Abstract 3876: The importance of spatial analysis and multispectral imaging when evaluating tumor-immune interactions in glioblastoma
Authors: Agnes E. Haggerty, Najiba Mammadova, Michael E. Barish, Christine E. Brown
Journal: Cancer Research (2022)

Abstract Glioblastoma (GBM) is an aggressive and almost universally fatal brain cancer. Glioblastoma tumor masses are highly vascularized and infiltrated with cells mediating both innate and adaptive immunity. The presence and organization of various immune cells within the tumor microenvironment varies between patients and within individual tumors. This variability in the immune landscape influences responses to different treatment modalities, including immunotherapies. Understanding reciprocal immune-tumor cell interactions will enhance design and implementation of novel therapies. Currently, review of GBM patient tissues by neuropathologists is done visually using single or low-plex biomarker panels whose complexity is constrained by limitations of traditional immunohistochemistry, including the lack of well characterized primary antibody clones, limited antibody selection due to species-dependent workflows, and inaccuracies such as false signal intensities introduced by autofluorescence (AF) and spectral overlap from traditional immunofluorescence imaging methods. Multiplex immunofluorescence (mIF) and multispectral imaging (MSI) allows for fast, accurate imaging on a single tissue section of up to eight fluorophores (using Phenoptics technology), cell type-specific AF spectra, and DAPI/Hoechst. It has been shown in other cancer types (i.e. lung cancer, breast cancer, melanoma) that spatial biology techniques including multiplex immunofluorescence is necessary to determine cellular densities and interactions in tissue context to better predict outcomes and stratify patient populations. Here, we have used pre-validated mIF kits that use Opal fluorophores together with the Vectra Polaris Automated Quantitative MSI system on human formalin-fixed, paraffin embedded GBM tissue samples to further characterize immune-tumor microenvironments, with consideration for spatial distributions of interacting cells. Pre-optimized immunofluorescent kits targeting immune cell subsets, checkpoint inhibitors, and other biomarkers have been shown to provide clinically relevant information in other cancer types (such as lung cancer and melanoma). Our study indicates that widespread use of these reagents, coupled with spatial analysis and complex phenotyping, would better characterize the complex immune landscape of tumors and enhance design and implementation of therapeutics for GBM. Citation Format: Agnes E. Haggerty, Najiba Mammadova, Michael E. Barish, Christine E. Brown. The importance of spatial analysis and multispectral imaging when evaluating tumor-immune interactions in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3876.
Abstract 2079: Tumor cell intrinsic inactivation of TREX1 increases type I IFN signaling and immune cell recruitment
Authors: Haritha Mathsyaraja, Benjamin Wolf, Chari Cortez, Adam Kashishian, Alison Karst, Madelyn Cueva, Min Wang, Kathleen S. Keegan, Jennifer Cain
Journal: Cancer Research (2022)

Abstract Tumor cells employ mechanisms to evade anti-tumor immune responses that can include the downregulation or silencing of cytosolic nucleic acid sensing pathway components to dampen Type I IFN signaling. It has been documented that genomic instability and mitotic stress in malignant cells can lead to aberrant cytosolic DNA accumulation and activation of the cGAS-STING pathway. A key negative regulator of cytosolic DNA is the DNA exonuclease TREX1. TREX1 assists in removing DNA from the cytosol, in turn reducing cGAS-STING mediated type I IFN induction. Not surprisingly, TREX1 is overexpressed in several tumor types when compared to normal tissue. The functional importance of TREX1 in cytoplasmic nucleic acid surveillance is evidenced by inactivating TREX1 mutations having an association with Type I inteferonopathies such as Aicardi-Goutières syndrome and SLE. Specifically, most of these mutations impact the enzymatic function of TREX1, underscoring the importance of its exonuclease function. To directly assess TREX1 function in cancer, we inactivated TREX1 in a panel of tumor cell lines. Loss of TREX1 resulted in reduced proliferation and increased expression of the Type I IFN-stimulated gene CXCL10. This finding was validated with CRISPR knockout of TREX1, which also led to the activation of IRF3 and a Type I IFN associated gene signature. To characterize the role of TREX1 function in curbing anti-tumor immunity in vivo, we inactivated Trex1 in the murine syngeneic B16F10 melanoma model. TREX1 knockout together with PD1 blockade resulted in slower tumor growth when compared to PD1 blockade alone. This was accompanied by an increase in CD8+ T and NK cell infiltration in tumors. In addition, gene expression profiling of whole tumors revealed that TREX1 loss resulted in increased type I IFN signaling within the tumor microenvironment. In summary, our data strongly suggest a critical role for TREX1 in suppressing anti-tumor immunity and indicate it would be an attractive target for therapeutic intervention. Citation Format: Haritha Mathsyaraja, Benjamin Wolf, Chari Cortez, Adam Kashishian, Alison Karst, Madelyn Cueva, Min Wang, Kathleen S. Keegan, Jennifer Cain. Tumor cell intrinsic inactivation of TREX1 increases type I IFN signaling and immune cell recruitment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2079.
Abstract 302: MEKi-FGFRi combination nanoparticles for use against KRASmt/FGFR-compensatory lung tumors
Authors: Arianna R. Izawa-Ishiguro, Ramya Sridharan, Christopher Wun, Tabassum J. Sami, Daniel A. Heller
Journal: Cancer Research (2022)

Abstract Targeting oncogenic signaling in the MAPK pathway can be achieved with small molecules such as trametinib, a MEK inhibitor (MEKi). Trametinib-induced MEK inhibition in KRAS-mutant (KRASmt) lung cancer, however, results in compensatory MAPK pathway re-activation through fibroblast growth factor receptor 1 (FGFR1). Combining MEK inhibition with FGFR1 inhibition should thereby combat this compensation; nonetheless, systemic administration of combination therapy faces its own set of challenges. Such challenges include delivering appropriate kinase inhibitor concentrations to target tumor tissue while avoiding dose-limiting additive toxicities. Although previous work has identified that combination therapy involving trametinib and FGFR inhibitor (FGFRi) ponatinib synergistically inhibits growth and proliferation of KRASmt cells, ponatinib interacts with a variety of targets and may mediate its synergistic effects via mechanisms not specific to FGFR1. To improve the efficacy at which we target KRASmt/FGFR-compensatory lung tumors, we encapsulated trametinib with a variety of FGFR1-specific inhibitors to form P-selectin-targeted nanoparticles. By formulating these nanoparticles, compensatory MAPK pathway activation through FGFR1 can be more efficaciously inhibited. Concurrently, greater concentrations of kinase inhibitor combinations can be locally delivered to lung tumors while mitigating toxic side effects that occur from systemic free drug. Here we show that these MEKi-FGFRi combination nanoparticles can be formulated to efficaciously inhibit growth and proliferation in KRASmt/FGFR-compensatory cancer cells. Citation Format: Arianna R. Izawa-Ishiguro, Ramya Sridharan, Christopher Wun, Tabassum J. Sami, Daniel A. Heller. MEKi-FGFRi combination nanoparticles for use against KRASmt/FGFR-compensatory lung tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 302.
Abstract 3188: Modulating UGDH expression in ovarian cancer tumor-initiating cells alters the tumor microenvironment
Authors: Brittney S. Harrington, Rahul Kamdar, Nathan Wong, Carrie D. House, Christina M. Annunziata
Journal: Cancer Research (2022)

Abstract Epithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix (ECM) and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, ECM synthesis enzyme UDP-glucose dehydrogenase (UGDH). Immunohistochemistry was used to delineate UGDH expression in histological and molecular subtypes of EOC. Clustering analysis was performed to characterize EOC cell lines to aligned to the molecular subtypes observed in tumors. UGDH expression was modulated in the cell lines using inducible shRNA, and the effects on TICs and on the cells in the supporting microenvironment were examined. High UGDH expression was observed in the majority of high-grade serous ovarian cancers and variable expression was observed in clear cell, mucinous and endometrioid histotypes. A distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype, where high UGDH was associated with a poor prognosis in the mesenchymal subtype. Using OV90 as a representative cell line for the mesenchymal subtype, we examined the effect of UGDH knockdown on the tumor cells alone, and on mesothelial support cells in co-culture with the tumor cells. Knock down of UGDH in the OV90 cells reduced the viability, sphere-formation and colony formation capacity of TICs and reduced extracellular hyaluronan production. Knocking down UGDH in the tumors affected the mesothelial cells in co-culture by significantly reducing the expression of ECM signaling and remodeling proteins Versican, Vitronectin, Laminin and matrix metalloprotease 1. These data show that modulation of UGDH expression in tumors influences cells in the microenvironment and reveal a distinct role for UGDH in the mesenchymal molecular subtype of EOC. UGDH is a strong prospective therapeutic target in TICs, for the treatment of metastatic and recurrent EOC, particularly in patients with the mesenchymal molecular subtype. Citation Format: Brittney S. Harrington, Rahul Kamdar, Nathan Wong, Carrie D. House, Christina M. Annunziata. Modulating UGDH expression in ovarian cancer tumor-initiating cells alters the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3188.
Abstract 1355: Lipid-rich foamy macrophages along with CD4 T cell-derived signaling drive aberrant lipid metabolism and are a cause of lung cancer development
Authors: Gongping Shi, Sayantan Banerjee, Xin Li, Gajendra Jogdand, Yongmei Zhao, Kunio Nagashima, Thorkell Andresson, Jyoti Shetty, Bao Tran, Yinling Hu
Journal: Cancer Research (2022)

Abstract Previously we reported that bone marrow-derived macrophages are required for lung squamous cell carcinoma development in kinase-dead Ikkα knockin (KA/KA) mice. The KA/KA lungs display strikingly enlarged sizes, sustained inflammation with increased expression of multiple cytokines and chemokines and marked infiltrating macrophages and T cells, and tissue damage, which look like a “burning hill”. To determine a critical event for the pathogenesis of the lung disease and SCC development, in this study, we found that these F4/80+CD11b+CSF1R+ monocyte-derived macrophages isolated from KA/KA lungs showed enlarged sizes carrying many lipid droplets and highly expressed the genes that encode proteins involved in lipid metabolism compared to WT. To determine whether the lung lipid concentrations regulate foamy macrophage development, we incubated Raw macrophages with WT or KA/KA lung extract, respectively, and found that KA/KA lung extracts induced lipid droplets and elevated lipid levels and pathways for lipid metabolism compared to WT lung extracts. Furthermore, we found that cytokines including IL-4, IL-6, IL-33, and IFNb, promoted lipid metabolism in Raw macrophages incubated with WT lung extracts, and also stimulated lipid metabolism in human lung SCC SW900 cells. These results suggest that these cytokines, which were highly expressed in KA/KA lungs, contribute to aberrant lipid metabolism. Because IL-4, which is produced by Th2 T cells, promoted lipid metabolism in macrophages and lung SCC cells, we further showed that KA/KA lung CD4 T cells stimulated lipid gene expression in Raw macrophages compared to WT lung CD4 T cells. Depleting CD4 T cells indeed significantly decreased foamy macrophage formation in the lungs of KA/KA mice. Importantly, treatment with a lipid inhibitor reduced IL-4-mediated lipid metabolism in Raw macrophages and human lung SCC SW900 cells, as well as this treatment attenuated lung foamy macrophage numbers and dampened lung SCC development in irradiated KA/KA mice with KA/KA bone marrow transplants. These findings highlight that the interplay between CD4 T cells, macrophages, cytokines, and epithelial cells contribute to a series of biological events in a landscape scale, which promote lung disease and lung SCC development through aberrant lipid metabolism. Citation Format: Gongping Shi, Sayantan Banerjee, Xin Li, Gajendra Jogdand, Yongmei Zhao, Kunio Nagashima, Thorkell Andresson, Jyoti Shetty, Bao Tran, Yinling Hu. Lipid-rich foamy macrophages along with CD4 T cell-derived signaling drive aberrant lipid metabolism and are a cause of lung cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1355.
Abstract 963: Targeting epithelial-mesenchymal plasticity via ribosome biogenesis inhibition reduces chemoresistant metastasis of breast cancer
Authors: Yi Ban, Wenjuan Dong, Yue Zou, Sharrell B. Lee, Jianting Sheng, Yuliang Cao, Stephen T.C. Wong, Dingcheng Gao
Journal: Cancer Research (2022)

Abstract Epithelial to mesenchymal transition (EMT) plays an important role in metastasis and chemoresistance. However, targeting EMT has been challenging due to the complex and redundant EMT signaling pathways. Moreover, EMT inhibition would unequivocally promote its reversed process, mesenchymal to epithelial transition (MET), which also favors malignancy progression. To solve this EMT targeting paradox, we proposed to target the ability of tumor cells to oscillate between epithelial and mesenchymal states, the epithelial to mesenchymal plasticity (EMP), which encompasses both EMT and MET. Using a SnailCre-ERT2 mediated EMT lineage-tracing model, we confirmed the involvement of EMP in chemoresistant metastasis of breast cancer. Single-cell transcriptome analyses of tumor cells in the transitioning phases of EMT or MET consistently revealed that ribosome biogenesis (RiBi) was specifically elevated regardless of their destined phenotypical fates. Further analyses delineated that the upregulation of RiBi and the subsequent nascent protein synthesis via the intensified ERK and mTOR signalings were vital for cancer cells to transit between epithelial and mesenchymal states. Importantly, inhibiting the excessive RiBi by either genetic or pharmacological means impaired EMP, as both EMT and MET processes were impeded, leading to significantly reduced metastatic outgrowth of chemoresistant tumor cells. Our studies revealed that elevated RiBi is required for tumor cells to “Ping Pong” between epithelial and mesenchymal states. Targeting the EMP via RiBi inhibition provides a feasible strategy to improve therapies for advanced breast cancers. Citation Format: Yi Ban, Wenjuan Dong, Yue Zou, Sharrell B. Lee, Jianting Sheng, Yuliang Cao, Stephen T.C. Wong, Dingcheng Gao. Targeting epithelial-mesenchymal plasticity via ribosome biogenesis inhibition reduces chemoresistant metastasis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 963.
Abstract 6135: Microbiome profiling through the various gastrointestinal environment of gastric cancer
Authors: Jieun Lee, Sunguk Shin, Seung-been Lee, Yieri Yoo, Sangjun Lee, So Hyun Kang, Eunju Lee, Young Suk Park, Sang-Hoon Ahn, Kyoung Un Park, Hyung-Ho Kim, Nak Jung Kwon, Yun-Suhk Suh
Journal: Cancer Research (2022)

Abstract The association between cancer and microbiome dysbiosis across anatomically related multiple body sites has not been comprehensively investigated. The purpose of our study is to profile microbial diversity and composition through the various gastrointestinal environment of gastric cancer (GC). We performed V3-V4 16S rRNA gene sequencing analysis for matched samples of gastric tumor, normal gastric mucosa, gastric juice and stool from 30 GC patients. Amplicon sequence variant (ASV) profile was compared among the four body sites at genus level. In this study, we found that mean alpha diversity was lowest in normal gastric mucosa and stool exhibited the largest amount of alpha diversity compared with others. Beta-diversity analysis showed significant differences in microbiota composition for each sample. The microbiome dysbiosis was significantly independent in gastrointestinal environment of gastric cancer. Helicobacter abundance in tumor tissue was significantly lower than in matched normal tissue and gastric juice while the trend was opposite for Lactobacillus. Additionally, the level of Helicobacter was considerably lower in patients with lymphatic invasion. The bacterial community that significantly correlated with tumor samples compared to normal mucosa, gastric juice, and stool were 49, 27, and 11 genus, respectively. Lactobacillus and Delftia had higher abundance and Rothia and Collnsella had lower abundance in tumor tissue compare with normal mucosa. Especially, Delftia was seen only in the tumor tissue not normal gastric mucosa, gastric juice and stool. Pentose phosphate pathway was significantly enriched in tumor tissue and normal mucosa. There is a unique microbiome pattern through the various gastrointestinal environment of gastric cancer. Our analysis shows enriched Delftia abundance only in the tumor tissue except other sample type. Citation Format: Jieun Lee, Sunguk Shin, Seung-been Lee, Yieri Yoo, Sangjun Lee, So Hyun Kang, Eunju Lee, Young Suk Park, Sang-Hoon Ahn, Kyoung Un Park, Hyung-Ho Kim, Nak Jung Kwon, Yun-Suhk Suh. Microbiome profiling through the various gastrointestinal environment of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6135.